Herpes simplex virus infection is the leading cause of sporadic fatal encephalitis worldwide and infectious blindness in the US. Transmission to the neonate is associated with high morbidity and mortality and an individual with genital HSV infection is 2-3 times more likely to acquire HIV. Once infected, there is currently no way to eliminate the latent viral genome, which persists for the life of the host and periodically reactivates producing infectious viral progeny that then is transmitted to new hosts. Considering that more than 70% of the world's population is currently infected with HSV, the direct and indirect impact of this virus to human health is profound. Despite this importance, our understanding of the viral/host interactions underlying the core aspects HSV pathogenesis in vivo, namely the establishment of and reactivation from latency, remains inadequate to direct the rationale design of preventative and treatment strategies. The long term goal of the proposed research is to understand those interactions between HSV and the nervous system which result in the establishment of latency and subsequent reactivation and the long term associated pathologies. Progress has been made in identifying key viral genes involved regulating latency, but the physiological changes in neurons that subvert or enhance the entry into and exit from latency are not understood. In this proposal we will pursue our important new observations that promyelocytic leukemia protein (PML) and the formation of PML-nuclear bodies (PML-NB) in neurons in vivo plays a central role in the establishment of latency and reactivation. Using state of the art quantitative in vivo methods, specific knock out mice, and HSV mutants we will: (1) Determine the role of PML and PML-NB formation in vivo on HSV: (i) lytic infection, (ii) establishment and maintenance of latent infections, and (iii) exit from latency and reactivation;and (2) Determine the biological significance of PML disruption by ICP0 in vivo: (i) during acute ganglion infection;and (ii) in sensory neurons during reactivation from latency. PUBLIC HEALTH RELEVANCE: We propose to determine the viral/host interactions that govern the establishment and maintenance of herpes simplex virus latency and periodic entry into the lytic replicative cycle. This knowledge will lead directly to improved design of vaccines, gene transfer vectors, oncolytic viruses to treat cancer, and may reveal new anti-viral targets.